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Optimization of the All-D peptide D3 for Aβ oligomer elimination

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Item Type:Article
Title:Optimization of the All-D peptide D3 for Aβ oligomer elimination
Creators Name:Klein, A.N. and Ziehm, T. and Tusche, M. and Buitenhuis, J. and Bartnik, D. and Boeddrich, A. and Wiglenda, T. and Wanker, E. and Funke, S.A. and Brener, O. and Gremer, L. and Kutzsche, J. and Willbold, D.
Abstract:The aggregation of amyloid-{beta} (A{beta}) is postulated to be the crucial event in Alzheimer's disease (AD). In particular, small neurotoxic A{beta} oligomers are considered to be responsible for the development and progression of AD. Therefore, elimination of thesis oligomers represents a potential causal therapy of AD. Starting from the well-characterized d-enantiomeric peptide D3, we identified D3 derivatives that bind monomeric A{beta}. The underlying hypothesis is that ligands bind monomeric A{beta} and stabilize these species within the various equilibria with A{beta} assemblies, leading ultimately to the elimination of A{beta} oligomers. One of the hereby identified d-peptides, DB3, and a head-to-tail tandem of DB3, DB3DB3, were studied in detail. Both peptides were found to: (i) inhibit the formation of Thioflavin T-positive fibrils; (ii) bind to A{beta} monomers with micromolar affinities; (iii) eliminate A{beta} oligomers; (iv) reduce A{beta}-induced cytotoxicity; and (v) disassemble preformed A{beta} aggregates. The beneficial effects of DB3 were improved by DB3DB3, which showed highly enhanced efficacy. Our approach yielded A{beta} monomer-stabilizing ligands that can be investigated as a suitable therapeutic strategy against AD.
Keywords:Amino Acid Sequence, Amyloid {beta}-Peptides, Enzyme-Linked Immunosorbent Assay, Oligopeptides, Tumor Cell Line, Animals, Rats
Source:PLoS ONE
ISSN:1932-6203
Publisher:Public Library of Science (U.S.A.)
Volume:11
Number:4
Page Range:e0153035
Date:22 April 2016
Official Publication:https://doi.org/10.1371/journal.pone.0153035
PubMed:View item in PubMed

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